Submissions for variant NM_001009944.3(PKD1):c.4051C>T (p.Arg1351Trp)

gnomAD frequency: 0.00551  dbSNP: rs55840049

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490456	SCV000267448	uncertain significance	Polycystic kidney disease, adult type	2016-03-18	criteria provided, single submitter	reference population
Mendelics	RCV000490456	SCV001139791	benign	Polycystic kidney disease, adult type	2023-08-22	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV001289050	SCV001476604	benign	not specified	2020-07-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001722138	SCV001949020	benign	not provided	2020-02-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22995991, 17574468, 17582161)
PreventionGenetics, part of Exact Sciences	RCV003982954	SCV004796082	benign	PKD1-related condition	2019-08-20	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292387	SCV001480840	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg1351Trp variant was identified in 2 of 568 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD (Rossetti_2007, Garcia-Gonzalez_2007). The variant was also identified in dbSNP (ID: rs55840049) “With Uncertain significance allele”, ClinVar (classified uncertain significance by Soonchunhyang University Bucheon Hospital), ADPKD Mutation Database (classified likely neutral), and not in COGR, LOVD 3.0, and PKD1-LOVD. The variant was identified in control databases in 466 of 275234 chromosomes (2 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 396 (1 homozygous) of 23852 chromosomes (freq: 0.02), Other in 7 of 6410 chromosomes (freq: 0.001), Latino in 28 of 34396 chromosomes (freq: 0.0008), European Non-Finnish in 10 of 125168 chromosomes (freq: 0.00008), East Asian in 23 (1 homozygous) of 18814 chromosomes (freq: 0.001), and South Asian in 2 of 30768 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish and European Finnish populations. The p.Arg1351 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, the variant was identified in our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.2494dupC, p.Arg832ProfsX40), increasing the likelihood it does not have clinical significance. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign.